While there is a substantial body of evidence that individual differences in response to cocaine are mediated, in part, by genetic factors, no single gene has been identified that can account for differential responsivity to cocaine. Recent studies in our laboratory may have moved us closer to the identification of the gene(s) underlying a number of cocaine's actions. We have identified several cocaine-related phenotypes on which 2 closely related substrains of C57BL mice (6J and 6ByJ) differ substantially. Among these are cocaine-induced locomoting and cocaine-induced seizures. The genealogy of these 2 substrains leads to the expectation that they should be genetically very similar, differing at only a few genetic loci. Thus, the large differences between the 2 substrains in cocaine responsivity probably are mediated by allelic differences for a single gene mediating cocaine's effects. As a first step towards identifying the gene(s) underlying cocaine-related phenotypes, we are proposing to conduct a series of genetic manipulaitons to further characterize the genetic architecture underlying the differences between the 2 substrains in cocaine sensitivity. We propose to conduct full buomerical analyses cocaine-induced locomoting and seizures using classical mendelian breeding strategies to determine the mode of inheritance of each behavior, estimate the number of genes mediating each phenotype and determine if the phenotypes are mediated by the same gene(s). We also propose to conduct an abbreviated from of a congenic breeding strategy to transfer the differential alleles underlying these 2 phenotypes onto the genetic backgrounds of the 2 substrains. This will allow us to further assess whether these behaviors are mediated by a single gene. These studies will provide a model for the furture production of congenic lines of mice segregating only at the genetic loci mediating cocaine sensitivity. We are also proposing to screen a battery of substrains related to the 3 strains of mice being used for RI-QTL mapping studies (C57, DBA & A) on these two cocaine-related phenotypes. These 3 studies will facilitate furture mapping of the gene(s) underlying cocaine's behavioral effects. Finally, we are planning to characterize any possible cocaine pharmacokinetic differences between the 2 strains that could account for their differential sensitivity to the drug. We also propose to characterize 2 neurotransmitter systems (glutamatergic and dopaminergic) in brain regions known to be associated with some of cocaine's pharmacological effects in the 6J and BhJ strains. These studies will contribute to the identification of risk factors for cocaine addiction and the development of preventative and therapeutic intervention strategies.